Functional network disruption in the degenerative dementias

Abstract

Despite considerable advances toward understanding the molecular pathophysiology of the neurodegenerative dementias, the mechanisms linking molecular changes to neuropathology and the latter to clinical symptoms remain largely obscure. Connectivity is a distinctive feature of the brain and the integrity of functional network dynamics is critical for normal functioning. A better understanding of network disruption in the neurodegenerative dementias may help bridge the gap between molecular changes, pathology and symptoms. Recent findings on functional network disruption as assessed with “resting-state” or intrinsic connectivity fMRI and EEG/MEG have shown distinct patterns of network disruption across the major neurodegenerative diseases. These network abnormalities are relatively specific to the clinical syndromes, and in Alzheimer's disease and frontotemporal dementia network disruption tracks the pattern of pathological changes. These findings may have a practical impact on diagnostic accuracy, allowing earlier detection of neurodegenerative diseases even at the pre-symptomatic stage, and tracking of disease progression.

ApoE ε4 Allele Related Alterations in Hippocampal Connectivity in Early Alzheimer’s Disease Support Memory Performance

“…Albeit being in line with our findings, all these studies were based on a localisation-based approach. This type of approach is not as suitable as a connectivity-based framework to characterise cellular and synaptic disruption, and its association to the underlying cognitive functions [66]. Moreover, it is worth noting that evidence emerging from connectivity analyses should not be taken for granted as the natural consequence of the aforementioned localisation-based differences reported in the literature.…”

P4–021: A hypnic hypothesis of Alzheimer's disease

“…The core function of the network continues to be defined, but it is active during stimulus-independent thought in the resting wakeful (and dreaming) brain [7,59,60] . Functional alterations in the DMN have been consistently identified in neuroimaging studies [6][7][8] of AD. Brainstem systems projecting to the DMN together with the DMN proper are likely to be integral to the development of AD; brainstem nuclei (in particular, the locus coeruleus) and ascending neurotransmitter systems comprise the 'isodendritic core' or reticular formation [66] and are among the earliest targets of AD pathology [1] .…”

“…The very earliest disease targets in AD remain somewhat contentious but are likely to include entorhinal cortex and brainstem sites, including locus coeruleus, dorsal raphe nuclei or nucleus tractus solitarius [2,8,84] . Consistent with the early disruption of circadian and sleep physiology observed clinically, neuropathological evidence in AD clearly implicates ascending brainstem pathways that govern the sleep-wake cycle at or near the outset of the disease, including cholinergic, dopaminergic, melatoninergic and neurosteroid systems [2,4,27,42,56,63] .…”

“…However, converging evidence drawn from molecular biology, sleep neuroscience [21][22][23][24][25][26][27][28][29][30][31][32][33][34] and clinical neurology [35][36][37][38][39][40][41][42] suggests that sleep may interact in diverse and important ways with the pathophysiology of AD. Ramifications of long-term disruption in the sleep-wake cycle could include synaptic overactivity and excitotoxicity [10,21,[43][44][45] , impaired synaptic pruning [46] , failure of synaptic scaling and homeostatic responses [19,20,27,[47][48][49][50][51] , transmission of pathogenic proteins (β-amyloid and tau) [9,15,16] , and disruption of neural circuitry in the vulnerable DMN [6,8,12,21,52,53] . Such alterations might in turn underpin or contribute to the cognitive syndrome that characterises AD.…”

“…Molecular biological, biochemical and neuroimaging studies have yielded a substantial body of data on the causes and evolution of AD [1][2][3][4][5] , whilst the concept of a vulnerable distributed brain network provides a framework for explaining how molecular events might scale up to a clinical phenotype [6][7][8][9] . It is increasingly clear that AD has a protracted prodromal phase prior to clinical onset during which potentially pathogenic factors could operate and might have cumulative effects [5] .…”